The overall goal of the Case Comprehensive Cancer Center (Case CCC) Developmental Therapeutics Program Phase I effort is to promote the discovery and evaluation of new, mechanism-based therapeutics for the cancer patient. The program brings together interactive teams of biochemists, molecular biologists, biochemical and clinical pharmacologists, cancer and vascular biologists, virologists, imaging scientists and radiologists, and clinical investigators around specific-mechanism-based targets and imaging technology platforms. New mechanism-based therapies discovered in model systems in a cooperative manner with NCI/CTEP, pharmaceutical partners, and in Cancer Center laboratories are evaluated for feasibility and efficacy in cancer patients by conducting investigator-initiated Phase I and II clinical trials. The Program also pursues development and identification of potential biomarkers to better inform and guide our developmental therapeutics pursuits. There are 3 mechanism-based therapeutic strategies that serve as the primary scientific focus for our Phase I investigative teams: (1) DMA metabolism and repair, (2) cancer angiogenesis, and (3) cell signaling and apoptosis. The Phase I Program benefits from all the scientific and clinical research resources of the Case CCC including the 9 scientific programs and pivotal core facilities (e.g., Translational Research, Clinical Trials, Biostatistics, Cancer Pharmacology, Athymic and Xenograft, Imaging Research, and Flow Cytometry Shared Resources). The Phase I program has provided national leadership to CTEP in the pursuit of mechanism-based early phase drug development, incorporated novel imaging strategies to monitor drug and target effects, developed novel biomarkers to guide drug development and therapeutics, and provided significant contributions to the CTEP Organ Dysfunction Working Group. During this past U01 funding cycle, investigators at the Case CCC contributed 250 patients to CTEP Phase I trials and another 254 patients to CTEP Phase II trials, predominantly with agents that were developed in the Phase I setting (e.g., O6- benzylguanine and rebeccamycin analog) by our group. It is the intent of this application to continue to build on this strong clinical translational research platform and, more importantly, to provide a resource for the cooperative evaluation of scientifically directed Phase I trials of promising anticancer agents available from the NCI drug screening program or referred to NCI from other sources. The Developmental Therapeutics Program looks forward to renewing its collaborative relationship with CTEP and other investigators in pursuit of the development of new anticancer agents with Phase I and select Phase II emphasis.